GRK6 deficiency in mice causes autoimmune disease due to impaired apoptotic cell clearance.
GRK6 deficiency in mice causes autoimmune disease due to impaired apoptotic cell clearance.
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DOI：
10.1038/ncomms2540
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发表时间：
2013
影响因子：
16.6
通讯作者：
中科院分区：
文献类型：
--
作者：
有效地吞噬凋亡细胞是维持组织内稳态的关键。当吞噬细胞识别出现在凋亡细胞表面的“Eat Me”信号时，这随后通过激活rac1诱导吞噬细胞的细胞骨架重排。然而，导致rac1激活的细胞内信号级联在很大程度上仍不清楚。在这里，我们展示了G蛋白偶联受体激酶6(GRK6)参与了细胞凋亡的清除。GRK6与GIT1协同激活rac1，它独立于DOCK180/Elmo/rac1和GULP1/rac1两个已知的吞噬途径促进细胞的凋亡吞噬。因此，GRK6基因缺陷的小鼠会患上一种自身免疫性疾病。GRK6缺乏的小鼠也增加了脾红髓中的铁储存，其中F4/80+巨噬细胞负责衰老的红细胞清除。我们的结果揭示了以前未知的GRK6在调节细胞凋亡吞噬中的作用，以及它在免疫和铁稳态中的基本重要性。巨噬细胞清除凋亡细胞对组织内稳态非常重要。在这里，Nakaya等人。揭示了GRK6在调节细胞凋亡吞噬中的作用，并表明GRK6缺乏会导致自身免疫性疾病和脾中铁的积聚。
Efficient engulfment of apoptotic cells is critical for maintaining tissue homoeostasis. When phagocytes recognize ‘eat me’ signals presented on the surface of apoptotic cells, this subsequently induces cytoskeletal rearrangement of phagocytes for the engulfment through Rac1 activation. However, the intracellular signalling cascades that result in Rac1 activation remain largely unknown. Here we show that G-protein-coupled receptor kinase 6 (GRK6) is involved in apoptotic cell clearance. GRK6 cooperates with GIT1 to activate Rac1, which promotes apoptotic engulfment independently from the two known DOCK180/ELMO/Rac1 and GULP1/Rac1 engulfment pathways. As a consequence, GRK6-deficient mice develop an autoimmune disease. GRK6-deficient mice also have increased iron stores in splenic red pulp in which F4/80+ macrophages are responsible for senescent red blood cell clearance. Our results reveal previously unrecognized roles for GRK6 in regulating apoptotic engulfment and its fundamental importance in immune and iron homoeostasis. The clearance of apoptotic cells by macrophages is important for tissue homoeostasis. Here Nakaya et al. reveal a role for GRK6 in the regulation of apoptotic engulfment and show that GRK6 deficiency in mice leads to autoimmune disease and iron accumulation in the spleen.
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DOI：
10.1083/jcb.201004096
发表时间：
2010-06-28
期刊：
The Journal of cell biology
影响因子：
--
作者：
Elliott MR;Ravichandran KS
通讯作者：
Ravichandran KS
DOI：
10.1073/pnas.83.10.3311
发表时间：
1986-05-01
影响因子：
11.1
作者：
MCEVOY, L;WILLIAMSON, P;SCHLEGEL, RA
通讯作者：
SCHLEGEL, RA
DOI：
10.1084/jem.20101709
发表时间：
2011-05-09
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Hashimoto D;Chow A;Greter M;Saenger Y;Kwan WH;Leboeuf M;Ginhoux F;Ochando JC;Kunisaki Y;van Rooijen N;Liu C;Teshima T;Heeger PS;Stanley ER;Frenette PS;Merad M
通讯作者：
Merad M
影响因子：
82.9
作者：
通讯作者：
--
影响因子：
11.4
作者：
Mandiyan, V;Andreev, J;Hubbard, SR
通讯作者：
Hubbard, SR